Impact of fatty acid desaturase 1 (FADS1) on chronic kidney disease via very low-density lipoprotein: A drug target-related mediation Mendelian randomization study.

IF 4.6 3区医学 Q2 PHARMACOLOGY & PHARMACY

Journal of clinical lipidology Pub Date : 2025-07-03 DOI:10.1016/j.jacl.2025.06.024

Yongdi Zuo, Lei Chen, Manrong He, Jingxue Du, Wanxin Tang

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引用次数: 0

Abstract

Background: Chronic kidney disease (CKD) is a globally prevalent condition and still lacks effective specific medications. Metabolic dysregulation plays a crucial role in CKD.

Objective: To Identify new potential targets for CKD through metabolites and their regulatory genes.

Methods: A total of 233 metabolites from the GWAS Catalog were utilized for Mendelian randomization (MR) with CKD. External validation was conducted from UK Biobank. Cis-eQTL of genes related to very low-density lipoprotein (VLDL) were selected for MR with CKD and metabolites. The total effect of the fatty acid desaturase 1 gene (FADS1) on CKD and metabolite-mediated effects were calculated. Bulk RNA-seq were used to validate FADS1 expression in the kidney tissues of patients with CKD.

Results: The cholesteryl esters to total lipids ratio in medium VLDL (odds ratio [OR] = 0.84; P.adj = .039) and total cholesterol to total lipids ratio in small VLDL (OR = 0.84; P.adj = .003) were protective factors for CKD, whereas the triglycerides to total lipids ratio in small VLDL (OR = 1.18; P.adj = .009) and the triglycerides to total lipids ratio in very small VLDL (OR = 1.1; P.adj < .001) were risk factors. They mediated the risk of CKD by FADS1 (OR = 1.1; P.adj = .001), and mediation effects of 21.17%, 10.43%, 23.52%, and 29.96%, respectively, were obtained. The differential expression of FADS1 was observed in the kidney tissues of patients with CKD.

Conclusion: FADS1 is a risk factor for CKD and a novel therapeutic target. Four metabolites mediate the detrimental effect of FADS1 in CKD.

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脂肪酸去饱和酶1 （FADS1）通过极低密度脂蛋白对慢性肾脏疾病的影响：一项药物靶标相关的孟德尔随机化研究

背景：慢性肾脏疾病（CKD）是一种全球流行的疾病，但仍然缺乏有效的特异性药物。代谢失调在CKD中起重要作用。目的：通过代谢产物及其调控基因寻找CKD新的潜在靶点。方法：利用GWAS目录中的233种代谢物对CKD进行孟德尔随机化（MR）。外部验证由UK Biobank进行。选择了与极低密度脂蛋白（VLDL）相关的顺式eqtl基因，用于CKD和代谢物的MR。计算脂肪酸去饱和酶1基因（FADS1）对CKD的总影响和代谢物介导的影响。使用Bulk RNA-seq验证CKD患者肾脏组织中FADS1的表达。结果：中等VLDL中胆固醇酯与总脂的比值(优势比[OR] = 0.84；p = 0.039)和小VLDL总胆固醇与总脂质比值(OR = 0.84；P.adj = 0.003)是CKD的保护因素，而小VLDL的甘油三酯与总脂的比值(OR = 1.18；P.adj = 0.009)和非常小的VLDL中甘油三酯与总脂的比值(OR = 1.1；P.adj < .001)为危险因素。它们通过FADS1介导CKD的风险(OR = 1.1；P.adj = .001)，中介效应分别为21.17%、10.43%、23.52%和29.96%。在CKD患者肾组织中观察到FADS1的差异表达。结论：FADS1是CKD的危险因素，是一种新的治疗靶点。四种代谢物介导FADS1在CKD中的有害作用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of clinical lipidology 医学-药学

CiteScore

7.00

自引率

6.80%

发文量

209

审稿时长

49 days

期刊介绍： Because the scope of clinical lipidology is broad, the topics addressed by the Journal are equally diverse. Typical articles explore lipidology as it is practiced in the treatment setting, recent developments in pharmacological research, reports of treatment and trials, case studies, the impact of lifestyle modification, and similar academic material of interest to the practitioner. Sections of Journal of clinical lipidology will address pioneering studies and the clinicians who conduct them, case studies, ethical standards and conduct, professional guidance such as ATP and NCEP, editorial commentary, letters from readers, National Lipid Association (NLA) news and upcoming event information, as well as abstracts from the NLA annual scientific sessions and the scientific forums held by its chapters, when appropriate.